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DLG4
DLG4
DLG4
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DLG4
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesDLG4, PSD95, SAP-90, SAP90, Dlgh4, PSD-95, SAP90A, discs large homolog 4, discs large MAGUK scaffold protein 4, MRD62
External IDsOMIM: 602887; MGI: 1277959; HomoloGene: 1047; GeneCards: DLG4; OMA:DLG4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1742

13385

Ensembl

ENSG00000132535

ENSMUSG00000020886

UniProt

P78352
O14909

Q62108

RefSeq (mRNA)
RefSeq (protein)

NP_001103222
NP_031890

Location (UCSC)Chr 17: 7.19 – 7.22 MbChr 11: 69.91 – 69.94 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

PSD-95 (postsynaptic density protein 95) also known as SAP-90 (synapse-associated protein 90) is a protein that in humans is encoded by the DLG4 (discs large homolog 4) gene.[5][6][7]

PSD-95 is a member of the membrane-associated guanylate kinase (MAGUK) family. With PSD-93 it is recruited into the same NMDA receptor and potassium channel clusters. These two MAGUK proteins may interact at postsynaptic sites to form a multimeric scaffold for the clustering of receptors, ion channels, and associated signaling proteins.[5] PSD-95 is the best studied member of the MAGUK-family of PDZ domain-containing proteins. Like all MAGUK-family proteins, its basic structure includes three PDZ domains, an SH3 domain, and a guanylate kinase-like domain (GK) connected by disordered linker regions. It is almost exclusively located in the post synaptic density of neurons,[8] and is involved in anchoring synaptic proteins. Its direct and indirect binding partners include neuroligin, NMDA receptors, AMPA receptors, and potassium channels.[9] It plays an important role in synaptic plasticity and the stabilization of synaptic changes during long-term potentiation.[10]

MAGUK superfamily and constituent domains

[edit]

PSD-95 (encoded by DLG4) is a member of the MAGUK superfamily, and part of a subfamily which also includes PSD-93, SAP97 and SAP102. The MAGUKs are defined by their inclusion of PDZ, SH3 and GUK domains, although many of them also contain regions homologous of CaMKII, WW and L27 domains.[11] The GUK domain that they have is structurally very similar to that of the guanylate kinases, however it is known to be catalytically inactive as the P-Loop which binds ATP is absent. It is thought that the MAGUKs have subfunctionalized the GUK domain for their own purposes, primarily based on its ability to form protein-protein interactions with cytoskeleton proteins, microtubule/actin based machinery and molecules involved in signal transduction.

The PDZ domain which are contained in the MAGUKs in varying numbers, is replicated three times over in PSD-95. PDZ domains are short peptide binding sequences commonly found at the C-terminus of interacting proteins. The three copies within the gene have different binding partners, due to amino acid substitutions within the PSD-95 protein and its ligands. The SH3 domain is again a protein-protein interaction domain. Its family generally bind to PXXP sites, but in MAGUKs it is known to bind to other sites as well. One of the most well known features is that it can form an intramolecular bond with the GUK domain, creating what is known as a GUK-SH3 'closed' state. The regulatory mechanisms and function are unknown but it is hypothesized that it may involve a hook region and a calmodulin binding region located elsewhere in the gene.

Interactions

[edit]

PSD-95 has been shown to interact with:

See also

[edit]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

DLG4

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from Grokipedia
DLG4 is a human gene located on the short arm of chromosome 17 (17p13.1) that encodes postsynaptic density protein 95 (PSD-95), also known as synapse-associated protein 90 (SAP-90), a member of the membrane-associated guanylate (MAGUK) family of proteins essential for synaptic organization. The PSD-95 protein is predominantly expressed in the , where it localizes to the postsynaptic density of excitatory synapses, forming multimeric scaffolds that cluster ionotropic receptors such as NMDA and receptors, potassium channels, and associated signaling molecules to regulate synaptic transmission and plasticity. This function is critical for , neuronal signaling, and processes underlying learning and memory, with PSD-95 heteromultimerizing with other MAGUK proteins like DLG2 to enhance synaptic stability. Pathogenic variants in DLG4, typically de novo heterozygous loss-of-function mutations such as frameshifts or variants, lead to DLG4-related synaptopathy (also known as SHINE ), an autosomal dominant . This condition is characterized by (present in 100% of reported cases, often mild to moderate), (84%), autism spectrum disorder (56%), or seizures (53%), (53%), and (46%), with additional features including disturbances, , joint hypermobility, and . The disorder arises from impaired synaptic function and plasticity due to of PSD-95, disrupting neuronal connectivity and development. Diagnosis is confirmed through molecular identifying DLG4 variants, and management focuses on supportive therapies for neurodevelopmental and behavioral symptoms.

Gene

Location and organization

The DLG4 gene, officially symbolized as DLG4 by the , encodes the discs large homolog 4 protein, also known as postsynaptic density protein 95 (PSD-95) or synapse-associated protein 90 (SAP90). Its accession number is P78352 for the human isoform. In humans, DLG4 is located on the short arm of chromosome 17 at band 17p13.1, spanning genomic coordinates 7,187,187 to 7,219,836 (GRCh38.p14 assembly, reverse strand). In mice, the orthologous Dlg4 gene resides on at coordinates 69,908,029 to 69,938,107 (GRCm39 assembly). The human DLG4 gene spans approximately 30 kb and consists of 22 s, with exon sizes ranging from 28 to 1,218 nucleotides; all intron-exon junctions follow the GT-AG rule. Alternative splicing of DLG4 produces multiple transcripts, including the primary isoforms PSD-95α (lacking an N-terminal insertion) and PSD-95β (containing a 24-amino-acid N-terminal extension encoded by 1β). These isoforms arise from the use of alternative first s, contributing to tissue-specific expression variations. DLG4 exhibits strong evolutionary conservation, particularly in mammals, with the encoded PSD-95 protein sharing 99% sequence identity between , , and orthologs. Orthologs are also present in , such as the discs large 1 (dlg1) , which shares functional and structural similarities as a founding member of the MAGUK family. This conservation underscores DLG4's essential role in synaptic organization across species.

Expression patterns

The DLG4 gene, encoding the postsynaptic density protein PSD-95, exhibits highly specific expression patterns predominantly within the . It is markedly enriched in brain neurons, with mRNA levels showing strong specificity to neural tissues compared to other organs. Within the brain, DLG4 expression is particularly prominent in the postsynaptic densities of excitatory synapses, serving as a key scaffold in regions such as the hippocampus and , where it supports synaptic organization and plasticity. This neuronal enrichment underscores its role in excitatory , with transcript levels detected across both gray and in adult brains. Developmentally, DLG4 expression follows a tightly regulated timeline aligned with . During embryonic stages, such as embryonic day 18 (E18) in , mRNA levels remain low, reflecting minimal synaptic maturation at this point. Postnatally, expression rises progressively, with significant upregulation observed from postnatal day 7 (P7) through P21 in brains, coinciding with peak periods of formation and strengthening in the hippocampus and cortex. This temporal pattern ensures that DLG4 is available to facilitate the assembly of postsynaptic complexes as neural circuits mature. Although primarily neuronal, DLG4 displays low-level expression in non-neuronal tissues, including the heart, lung, and testis, as evidenced by transcriptome data from human samples. Emerging studies also indicate detectable expression in non-neural cells, such as epithelial tissues, where an alternatively spliced form of DLG4 may contribute to cellular polarization and organization. DLG4 expression is governed by specific promoters and enhancers that respond to developmental and environmental cues. In neurons, it is influenced by activity-dependent mechanisms, including signaling through CREB transcription factors, which integrate synaptic inputs to modulate transcript levels during plasticity and circuit refinement.

Protein

Primary structure

The DLG4 gene encodes the postsynaptic density protein 95 (PSD-95), a member of the membrane-associated guanylate kinase (MAGUK) . The canonical isoform, PSD-95α, consists of 724 with a calculated molecular weight of approximately 80.5 kDa, though the observed molecular weight is around 95 kDa due to post-translational modifications. The protein sequence features two N-terminal cysteine residues (Cys3 and Cys5) in PSD-95α that are subject to palmitoylation, facilitating membrane association.00793-7) Two major isoforms of PSD-95 are produced through of the N-terminal region: PSD-95α and PSD-95β. PSD-95α includes a short N-terminal sequence with the palmitoylation motif, comprising the full 724 and representing the predominant form in the (about 80-90% of expression). In contrast, PSD-95β features an alternative N-terminal extension of 53 containing an L27 domain for protein-protein interactions, lacking the palmitoylation cysteines, and results in a slightly shorter protein of approximately 711 . This isoform-specific splicing occurs via mutually exclusive use of exons encoding the N-terminal regions, with PSD-95β generated by inclusion of β-specific exons (β1, β1', β1"). A truncated isoform also exists but is less abundant. Post-translational modifications of PSD-95 include palmitoylation, , and ubiquitination. In PSD-95α, palmitoylation occurs dynamically at Cys3 and Cys5, enabling synaptic targeting and cycling. targets multiple serine and residues, such as Ser295 (S295) in the linker region between PDZ domains, mediated by calcium/calmodulin-dependent II (CaMKII), along with other sites like Ser73 (S73) and Thr19 (T19). Ubiquitination occurs on residues, primarily regulated by E3 ligases like , marking the protein for proteasomal degradation without specified dominant sites but affecting overall stability.00793-7) As a MAGUK family member, PSD-95 exhibits sequence homology to other proteins like PSD-93 (DLG2) and SAP97 (DLG1), particularly in conserved regions encompassing the three PDZ domains (approximately 80-90 residues each), the SH3 domain, and the guanylate kinase (GK)-like domain, which together comprise about 60% of the protein length and share 70-90% identity across MAGUKs.

Domains and motifs

The PSD-95 protein, encoded by the DLG4 gene, belongs to the membrane-associated guanylate kinase (MAGUK) superfamily of proteins, which are characterized by a conserved PDZ-SH3-GK modular cassette that facilitates the organization of multiprotein complexes at cellular membranes. This architecture enables PSD-95 to act as a core organizer in postsynaptic densities, linking transmembrane receptors to intracellular signaling and cytoskeletal elements. PSD-95 contains three tandem N-terminal PDZ domains (PDZ1, PDZ2, and PDZ3), each approximately 80-90 long, which recognize and bind short C-terminal motifs (typically -X-S/T-X-Φ, where Φ is a hydrophobic residue) on target proteins. PDZ1 and PDZ2 preferentially interact with the C-terminal motifs of auxiliary subunits like stargazin, which traffics receptors to synapses, while PDZ3 binds the -ESDV motif at the of neuroligin-1, promoting trans-synaptic adhesion. The central SH3 domain of PSD-95, comprising about 70 residues with a typical β-barrel fold, is positioned between PDZ3 and the GK domain and binds proline-rich sequences (P-X-X-P motifs) in partner proteins such as the SAPAP family (also known as GKAPs or DLGAPs). This interaction, though secondary to GK-mediated binding in some cases, contributes to the recruitment of cytoskeletal regulators. The C-terminal guanylate kinase (GK) domain, homologous to guanylate kinase but catalytically inactive due to key substitutions (e.g., in the ATP-binding site), adopts a bilobal structure and primarily functions in protein-protein interactions rather than . It binds the C-terminal regions of GKAPs/SAPAPs with micromolar affinity (e.g., K_d ≈ 1-2 μM) and mediates homodimerization of PSD-95 molecules through a conserved interface, stabilizing synaptic scaffolds. In addition to the core MAGUK cassette, PSD-95 features an N-terminal L27 domain in its β isoform, a ~120-residue module that promotes multimerization and heterodimerization with other L27-containing proteins like SAP97, enhancing synaptic clustering. The protein's extreme includes a PDZ-binding motif that enables intermolecular oligomerization by engaging the PDZ domains of adjacent PSD-95 molecules, further amplifying scaffold assembly.

Function

Synaptic scaffolding

PSD-95, the protein encoded by the DLG4 gene, serves as a primary scaffolding molecule in the postsynaptic density (PSD) of excitatory synapses, where it organizes and stabilizes a multitude of synaptic components essential for neuronal communication. Localized to the PSD through N-terminal palmitoylation, PSD-95 forms clusters that anchor ionotropic glutamate receptors, thereby maintaining the structural integrity of the postsynaptic apparatus. This localization enables PSD-95 to directly and indirectly cluster N-methyl-D-aspartate (NMDA) receptors and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors at synaptic sites, facilitating their proper positioning and synaptic efficacy. During synapse maturation, PSD-95 plays a critical role in promoting formation and stabilization, particularly in developing neurons. By organizing the PSD scaffold, it supports the transition from immature to mature mushroom-shaped spines, which is vital for assembly and overall circuit refinement. PSD-95 also regulates receptor trafficking by directing the insertion of glutamate receptors into the plasma membrane and modulating their through specific motifs, ensuring dynamic control over synaptic strength without delving into downstream signaling. These functions rely on PSD-95's modular domains, such as PDZ motifs, which facilitate its anchoring capabilities (detailed in the Protein section). Evidence from animal models underscores PSD-95's indispensable role in synaptic organization. In PSD-95 mice, density is reduced by 15% in the but increased by approximately 40% in the hippocampus. Additionally, these mutants exhibit altered (LTP), with enhanced LTP induction that impairs learning. Knockdown studies further confirm that PSD-95 deficiency arrests development, reducing functional numbers and PSD size.

Signal transduction

PSD-95, encoded by the DLG4 gene, plays a central role in coupling NMDA receptor (NMDAR) activation to downstream Ras/ERK signaling pathways through its PDZ domains. By binding the C-terminal tails of NMDAR subunits (primarily NR2A and NR2B) via PDZ1 and PDZ2, PSD-95 scaffolds the receptor in proximity to regulatory proteins like SynGAP, a Ras GTPase-activating protein (GAP) that associates with PSD-95's C-terminal region. Upon NMDAR activation and calcium influx, this complex modulates Ras activity; SynGAP negatively regulates Ras-ERK signaling to fine-tune synaptic plasticity, preventing excessive activation that could disrupt balanced neurotransmission. Disruption of this PDZ-mediated linkage impairs ERK phosphorylation and alters synaptic strengthening. In modulation, PSD-95 facilitates the phosphorylation of the GluA1 subunit and subsequent synaptic strengthening during (LTP). PSD-95 interacts with transmembrane AMPA receptor regulatory proteins (TARPs), such as stargazin, which bind the GluA1 and link it to PSD-95's PDZ domains, stabilizing s at the . This scaffolding enables kinases like CaMKII to phosphorylate GluA1 at Ser831, enhancing channel conductance and promoting AMPA receptor insertion into the postsynaptic membrane, a key step in LTP induction. Such interactions ensure activity-dependent trafficking and potentiation of AMPA-mediated currents, supporting synaptic efficacy. PSD-95 also orchestrates by scaffolding ion channels and kinases, notably linking NMDARs to neuronal (nNOS) via its PDZ2 domain. The C-terminal PDZ-binding motif of nNOS binds PSD-95's PDZ2, positioning nNOS near calcium-permeable NMDARs to sense influx upon activation. This proximity activates nNOS to produce (NO), which diffuses to activate soluble in adjacent cells, elevating cyclic GMP (cGMP) levels and modulating downstream targets like protein kinases for synaptic modulation. This pathway supports local calcium-dependent signaling without requiring direct enzymatic coupling. PSD-95 is critical for hippocampal-dependent learning and , particularly spatial tasks, as evidenced by deficits in DLG4 models. Mice lacking PSD-95 exhibit impaired performance in spatial learning paradigms, such as the Morris water maze, despite enhanced LTP, indicating a regulatory role in translating into behavioral outcomes. These disruptions highlight PSD-95's necessity for balancing excitability and in the hippocampus.

Pathophysiology

Disease associations

DLG4-related synaptopathy, also known as SHINE syndrome, is a rare primarily caused by heterozygous loss-of-function variants in the , leading to impaired synaptic scaffolding essential for neuronal communication. The condition was first described in 2021 through the identification of pathogenic variants in cohorts screened for , autism spectrum disorder, and related neurodevelopmental issues. Core clinical features include (affecting approximately 84% of cases), (in 100% of reported individuals, typically mild to moderate), and autism spectrum disorder traits (observed in 56%). Language delays are prominent, often manifesting as delayed speech acquisition and expressive impairments, alongside social communication challenges. Epilepsy is a significant , occurring in about 50-53% of affected individuals, with onset typically around age 6 years and encompassing both generalized and types. A notable subset involves developmental epileptic (DEE), particularly electrical in sleep (ESES) or DEE with spike-wave activation during sleep (DEE-SWAS), affecting more than 25% of those with and contributing to further neurodevelopmental regression. These epileptic phenotypes often correlate with sleep disturbances (in 45% of cases) and may exacerbate cognitive and behavioral challenges. Additional phenotypes include (53%), motor delays (such as gait abnormalities and coordination issues in 46%), and behavioral concerns like attention-deficit/hyperactivity disorder (57%) and anxiety (53%). Less common features encompass joint laxity (37%), (20%), , and vomiting (29%), with some individuals displaying a Marfanoid habitus. Intellectual regression, involving loss of previously acquired motor or skills, occurs in approximately one-third of cases, as highlighted by a 2024 report of a novel de novo frameshift variant (c.554_563del) in a child with onset at age 2. The disorder is ultra-rare, with fewer than 130 reported cases worldwide as of 2024, though exact remains unknown due to underdiagnosis. Variants are predominantly de novo and heterozygous, with loss-of-function mechanisms accounting for the majority, supporting an autosomal dominant inheritance pattern.

Pathogenic mechanisms

Pathogenic variants in DLG4 primarily lead to loss-of-function effects through , resulting in reduced PSD-95 protein levels that impair synaptic stability and the clustering of postsynaptic receptors such as and NMDA types. This reduction disrupts the scaffolding role of PSD-95 at excitatory s, leading to diminished synapse maturation and maintenance, as evidenced by decreased synaptic density and altered excitatory transmission in cellular models. Reported DLG4 variants include frameshift and nonsense mutations that trigger , such as the de novo heterozygous nonsense variant c.1840C>T (p.Arg614*), which was classified as likely pathogenic and associated with . Missense variants often affect critical PDZ domains, disrupting protein-protein interactions essential for synaptic organization, while frameshifts like c.554_563del (p.Gly185AlafsTer4) further contribute to protein truncation and functional loss. These variant types collectively support a dominant-negative or haploinsufficient mechanism, with most occurring de novo. At the synaptic level, DLG4 disruptions cause deficits including reduced and NMDA receptor-mediated currents, abnormal morphology with fewer mature spines, and impaired , as observed in Dlg4 models and inferred from human variant studies. Patient-derived neurons harboring DLG4 variants exhibit similar impairments, with decreased excitatory postsynaptic currents and disrupted , highlighting a core synaptopathy. Recent studies from 2023 to 2025 have linked DLG4 variants to developmental epileptic encephalopathy (DEE), particularly encephalopathy with during (ESES), where abnormal oscillations correlate with cognitive regression due to disrupted synaptic . In animal models of Dlg4 deficiency, cognitive and motor deficits, such as impaired learning and coordination, are reversible upon restoration of PSD-95 expression via epigenetic editing or artificial transcription factors, underscoring the potential for targeted therapeutic interventions.

Interactions

Direct binding partners

PSD-95, encoded by the DLG4 gene, interacts directly with several key synaptic proteins through its modular domains, primarily the PDZ domains, which recognize specific C-terminal motifs in binding partners. Members of the neuroligin family, such as neuroligin-1, bind to the third PDZ domain (PDZ3) of PSD-95 via their C-terminal -HV motif, a class I PDZ-binding sequence that facilitates postsynaptic and synapse specificity. This interaction is crucial for recruiting PSD-95 to nascent synapses during excitatory . For glutamate receptors, the NR2B subunit of NMDA receptors binds directly to the second PDZ domain (PDZ2) of PSD-95 through its C-terminal ES DV motif, enabling receptor clustering at the postsynaptic density. In contrast, receptors do not bind PSD-95 directly but associate indirectly via the auxiliary subunit stargazin, whose C-terminal TVI motif interacts with PDZ3 of PSD-95 to stabilize localization at synapses. Shaker-type channels, including Kv1.4, bind to the PDZ domains of PSD-95 (primarily PDZ1 and PDZ2) via their C-terminal tSXV motif, promoting channel clustering in the postsynaptic membrane. Among scaffolding proteins, the SAPAP family (also known as guanylate kinase-associated proteins or GKAPs) interacts with PSD-95 through multiple interfaces: SAPAPs bind the SH3 domain via proline-rich regions, while GKAP specifically engages the guanylate kinase (GK) domain, linking PSD-95 to cytoskeletal elements like Shank. These bindings, which leverage the modular of PSD-95 described in the protein section, support the assembly of postsynaptic scaffolds.

Regulatory complexes

PSD-95 forms a ternary complex with N-methyl-D-aspartate receptors (NMDARs) and neuronal (nNOS), which couples glutamate-mediated synaptic activation to (NO) production. In this complex, PSD-95's PDZ domains bind the C-terminal tails of NMDAR subunits GluN2A and GluN2B, while also interacting with the PDZ domain of nNOS, thereby tethering nNOS to the postsynaptic density (PSD) for efficient activation upon calcium influx through NMDARs. This linkage facilitates NO synthesis, which acts as a retrograde messenger to modulate presynaptic release and contribute to , such as (LTP), by influencing cyclic GMP signaling in target neurons. Additionally, nNOS-derived NO from this complex promotes by diffusing to adjacent vascular cells, thereby regulating cerebral blood flow in response to neuronal activity. Another key regulatory complex involves PSD-95 and the SAP90/PSD-95-associated proteins (SAPAPs, also known as DLGAPs or GKAPs), which bridge the PSD to the for dendritic spine stabilization. SAPAPs bind directly to the guanylate kinase-like (GK) domain of PSD-95, while their C-terminal regions interact with Shank proteins, which in turn recruit actin-binding partners like cortactin and to anchor the . This PSD-95/SAPAP/Shank maintains spine morphology and integrity by linking ionotropic glutamate receptors to F-actin dynamics, preventing spine shrinkage or loss under basal conditions and supporting structural plasticity. Disruptions in this complex, such as SAPAP mutations, lead to altered spine density and synaptic scaling, underscoring its role in organizing the postsynaptic architecture. The neuroligin-PSD-95 system coordinates with the β-catenin-containing complex to mediate trans-synaptic and modulate Wnt signaling at excitatory . Neuroligins, postsynaptic molecules, bind extracellularly to presynaptic neurexins to initiate formation, while their intracellular tails interact with PSD-95's PDZ domains to recruit scaffolding elements. β-Catenin associates with this assembly via interactions with cadherins, stabilizing and facilitating trans-synaptic bridging that aligns pre- and postsynaptic specializations. This coordination also integrates Wnt/β-catenin signaling, where stabilized β-catenin translocates to influence for synaptic proteins, thereby fine-tuning strength and maturation. These regulatory complexes exhibit dynamic assembly and disassembly in response to synaptic activity, particularly during LTP, mediated by calcium/calmodulin-dependent II (CaMKII) phosphorylation of PSD-95. Upon LTP induction, CaMKII phosphorylates PSD-95 at serine 73 within its N-terminal domain, promoting transient PSD destabilization that allows receptor trafficking and spine enlargement before restabilization. This phosphorylation-dependent remodeling enables activity-induced reconfiguration of complex components, such as enhanced recruitment of NMDARs to the PSD-95/nNOS module or SAPAP-mediated cytoskeletal adjustments, ensuring adaptive synaptic strengthening without chronic disruption.

References

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